Acute leukemia is typically a rapidly progressing leukemia characterized by replacement of normal bone marrow by blast cells of a clone arising from malignant transformation of a hematopoietic stem cell. There are two types of acute leukemias, acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML). ALL is the most common malignancy in children, but also occurs in adolescents and has a second, lower peak in adults. AML, also know as acute myeloid leukemia and acute myelocytic leukemia, is the more common acute leukemia in adults and its incidence increases with age, but AML also occurs in children. For both types of acute leukemias, the primary goal of treatment is to achieve complete remission, with resolution of abnormal clinical features, return to normal blood counts and normal hematopoiesis in the bone marrow with <5% blast cells, a neutrophil count of >1,000-1,500, a platelet count of >100,000, and disappearance of the leukemic clone; however, the drug regimens for treating ALL and AML have differed. The Merck Manual, Sec. 11, Ch. 138 (17th ed. 1999); Estey, E., Cancer (2001) 92(5): 1059-1073. Initial therapy aims at inducing remission. Treatment of AML differs most from ALL in that patients with AML respond to fewer drugs and have a high rate of relapse.
Patients with AML who achieve a complete remission live longer than patients who do not, and only patients who achieve complete remission are potentially cured if their complete remission remains for at least three years. Estey, E., Cancer (2001) 92(5): 1059, 1060. Remission induction rates in patients with AML range from 50 to 85%, with patients older than 50 years, and especially those older than 65 years, less likely to achieve remission. Long-term disease-free survival occurs in a low percentage of patients, 20-40%, and increases to 40-50% in younger patients treated with bone marrow transplants. Patients with secondary AML have a poor prognosis. The Merck Manual, Sec. 11, Ch. 138 (17th ed. 1999).
Treatment of AML is problematic because normal stem-cell precursors are sensitive to the agents used, and therapy aimed at myeloid leukemic clones results in destruction of part of the normal stem-cell pool. Induction of remission is usually possible with intensive chemotherapy. Complete remission has been stated to be achievable in up to 80% of younger patients and about 50% of older patients (who form the majority of those with AML), but patients suffer severe neutropenia during induction and remission rate is to some extent dependent upon the standard of supportive care. Remission rates are lower in those with adverse prognostic factors such as poor performance status, AML secondary to myelodysplasia or antineoplastics, high white cell count, features of multidrug resistance, and unfavorable cytogenetics. Löwenberg, B., et al., N. Engl. J. Med. (1999) 341:1051-62; Correction. ibid.; 1484. The greatest unmet medical need is in AML patients over 70 years of age. For these elderly AML patients, complete remission may be difficult to obtain, but an increased benefit in their quality of life is a treatment goal to be achieved.
Established regimens are based on cytarabine, a pyrimidine nucleoside analog, with the anthracycline daunorubicin. Löwenberg, B., et al., N. Engl. J. Med. (1999) 341:1051-62; Correction. ibid.; 1484; Burnett, A. K. & Eden O. B., Lancet (1997) 349:270-275; Hiddemann, W., et al., J. Clin. Oncol. (1999) 17:3569-76. The first successful regimens also included thioguanine, which is still used by some medical centers, although the majority opinion is that it gives no additional advantage and thioguanine has been dropped from most induction protocols. Alternatives to daunorubicin include idarubicin and mitoxantrone. Löwenberg, B., et al., N. Engl. J. Med. (1999) 341:1051-62; Correction. ibid.; 1484. Etoposide has been added to induction protocols of cytarabine and daunorubicin with improved results in younger patients.
The basic induction regimen for treatment of AML includes administration of cytarabine by continuous intravenous (IV) infusion for 7 days, with an anthracycline such as daunorubicin or idarubicin given IV for 3 days during this time, usually in the first three days. The Merck Manual, Sec. 11, Ch. 138 (17th ed. 1999). This widely used regimen for the treatment of AML is known as a 3+7 regimen and produces complete remission rates of 60-80%. De Nully Brown, P., et al., Leukemia (1997) 11:37-41. Treatment usually results in significant myelosuppression, often for long periods before marrow recovery. Other adverse events from these two drugs include chemical arachnoiditis, myocardial toxicity, and neurotoxicity. The induction regimen may be repeated, usually up to a total of three times, to achieve remission. Before repeating the induction regimen, a bone marrow analysis is done on after fourteen days from the completion of the last induction regimen. If the bone marrow has been cleaned out, i.e., there is a complete response, then the physician will wait until the patient's peripheral blood counts recover before administering another induction regimen. If the bone marrow analysis shows that disease is still present, i.e., there is a partial or minimal response, then the induction regimen will be repeated without waiting for the patient's peripheral blood counts to recover. The waiting period between induction regimens is therefore twenty-eight to thirty-five days for a complete responder, and fourteen to twenty-one days for partial and minimal responders. For patients with relapsed AML, the standard induction therapy of cytarabine and daunorubicin does not produce a good response rate, typically <40%, and the prognosis is poor for these patients.
After remission is achieved, a second treatment regimen using the same drugs or other drugs to knock out the disease, known as consolidation therapy, may be employed. However, a high percentage of patients suffer from relapse, even in series with intensive post-remission consolidation chemotherapy. De Nully Brown, P., et al., Leukemia (1997) 11:37-41.
The current trend is towards the use of more intensive induction regimens. Use of high-dose cytarabine in doses of up to 3 g/m2 every twelve hours for up to six days per day (with daunorubicin and etoposide) has been reported to improve the duration of first remission and disease-free survival compared with standard doses of cytarabine. Bishop, J. F., et al., Blood (1996) 87:1710-1717. Equally the timing of induction cycles may be important: intensive timing (where the second cycle was given 10 days after the first) has improved disease-free survival, despite more toxicity-related deaths, compared with the standard interval of 14 days or more. Woods, W. G., et al., Blood (1996) 87:4979-4989.
Once remission is induced, further treatment (post remission therapy) is essential in preventing relapse. Löwenberg, B., et al., N. Engl. J. Med. (1999) 341:1051-62; Correction. ibid.; 1484; Burnett, A. K. & Eden O. B., Lancet (1997) 349:270-275; Hiddemann, W., et al., J. Clin. Oncol. (1999) 17:3569-76. Options include further chemotherapy, or allogeneic or autologous bone marrow transplantation. Long-term survival of about 50% may be possible with these options when used in patients in first remission. However, which option to use is controversial. The most successful chemotherapy regimens use high-dose cytarabine for up to 4 courses, and appear to be comparable to bone marrow transplantation in terms of survival. Mayer, R. J. et al., N. Engl. J. Med. (1994) 331:896-903; Cassileth, P. A., et al., N. Engl. J. Med. (1998) 339:1649-1656. Consequently, some advocate a policy of intensive post remission chemotherapy, reserving transplantation for subsequent relapse, particularly for patients with favorable cytogenetics. Edenfield, W. J. & Gore, S. D., Semin. Oncol. (1999) 26:21-34.
Another drug used in the treatment of AML is gemtuzumab ozogamicin (Mylotarg®). Gemtuzumab ozogamicin was approved in May 2000 in the United States of America for the treatment of AML in patients in first relapse who are 60 years old or older and not considered candidates for other cytotoxic chemotherapy. Gemtuzumab ozogamicin is administered as a two-hour IV infusion in a dose of 9 mg/m2. A second dose may be administered fourteen days later. While many patients receiving gemtuzumab ozogamicin have achieved complete remission, a significant number of patients have had a delay in platelet recovery or incomplete platelet recovery. Physician's Desk Reference (56th ed. 2002). Hepatic venoocclusive disease (VOD), which is potentially fatal, has occurred in patients who have undergone stem cell transplantation after gemtuzumab ozogamicin therapy. Tack, D. K. et al., Bone Marrow Transplantation (2001) 28(9):895-897. It was also reported in July 2001 that patients receiving gemtuzumab ozogamicin who did not undergo stem cell transplantation developed as much as a 10% increased risk of developing significant hepatotoxicity and possible morbidity and mortality, although most of these patients received gemtuzumab ozogamicin in previously untested combinations or outside the approved labeled use. Giles, F. J., et al., Cancer (2001) 92(2):406-413. Like the standard cytarabine-daunorubicin induction therapy, the response rate of patients with relapsed AML to gemtuzumab ozogamicin therapy can be <40%.
Combination therapies with gemtuzumab ozogamicin have been tried with limited success. In one study, gemtuzumab ozogamicin was administered to elderly patients previously untreated for AML by 2-hour IV infusion at a dose of 9 mg/m2 on day 1 and 15, with MICE (mitoxantrone, cytarabine and etoposide) being given for one or two courses within seven days from the response assessment to gemtuzumab ozogamicin (between day 28 and 35 following the last infusion). Significant non-hematologic adverse events included, among others, VOD (6%), arrhythmia (6%), and infection (24%). At the end of the whole induction program, thirteen patients were in complete remission (38.2%) and 3 achieved a complete remission with incomplete platelet recovery (8.8%) for an overall response rate of 47%, not an improvement over existing therapies for AML. Amadori, S., et al., “Sequential Administration of Gemtuzumab Ozogamicin (GO) and Intensive Chemotherapy for Remission Induction in Previously Untreated Patients with AML over the Age of 60: Interim Results of the EORTC Leukemia Group AML-15A Phase II Trial,” Blood (2001) 98:587a.
In another study, patients with poor prognosis AML (>70 years age, myelodysplasia, leukemia developing after toxic exposure) were either treated under a protocol designated “AML 9503” in which the patient received two “pulses” of chemotherapy each consisting of 2 gm/m2 of cytarabine (a high dose of cytarabine) administered at time=0 and time=12 hours and mitoxantrone in an amount of 35 mg/m2 immediately after the second cytarabine dose, with the second “pulse” being given 96 hours later, or were treated under a protocol designated “AML 9798” in which the patient received two “pulses” of chemotherapy each consisting of 2 gm/m2 of cytarabine administered at time=0 and time=12 hours and mitoxantrone in an amount of 35 mg/m2 immediately after the second cytarabine dose, with the second “pulse” being given 96 hours later, followed by administration of amifostine. The complete remission rate for AML 9503 was 30% and for AML 9798 was 40%. When the chemotherapy was changed to add a single dose of gemtuzumab ozogamicin in an amount of 9 mg/m2 three days prior to the first pulse of chemotherapy, two of four such treated patients with refractory AML entered complete remission. Preisler, H, D., et al., “Synergistic Antileukemia Effects of Mylotarg and Chemotherapy in AML,” Blood (2001) 98:193b.
In a feasibility study, patients <60 years of age received H-DAT 3+10 regimen (daunorubicin 45 mg/m2 days 1, 3, 5; cytarabine 400 mg/m2 bd days 1-10; thioguanine 100 mg/m2 bd days 1-10) with gemtuzumab ozogamicin (3 or 6 mg/m2 given as a 2-hour infusion on day 1). The second course given was H-DAT 3+8 with the same gemtuzumab ozogamicin dose as in course 1. While both the 3 mg/m2 and 6 mg/m2 doses of gemtuzumab ozogamicin were tolerated in these two regimens, increased liver toxicity was seen when gemtuzumab ozogamicin was given at 6 mg/m2 in the first course and it was decided to thereafter use 3 mg/m2 of gemtuzumab ozogamicin in courses 1 and 2. Kell, J. W., et al., “Effects of Mylotarg™ (Gemtuzumab Ozogamicin, GO) in Combination with Standard Induction Chemotherapy in the Treatment of Acute Myeloid Leukaemia (AML): A Feasibility Study,” Blood (2001) 98:123a-124a.
In a further study, patients <60 years of age were given H-DAT 3+10 (daunorubicin 50 mg/m2 daily by slow IV push on days 1, 3, 5; cytarabine 200 mg/m2 IV push bd days 1-10; thioguanine 100 mg/m2 bd oral days 1-10) or S-DAT 3+10 (daunorubicin 50 mg/m2 daily by slow IV push on days 1, 3, 5; cytarabine 100 mg/m2 IV push bd days 1-10; thioguanine 100 mg/m2 bd oral days 1-10) with 3 or 6 mg/m2 gemtuzumab ozogamicin as induction therapy. A second course of H-DAT 3+8 (daunorubicin 50 mg/m2 daily by slow IV push on days 1, 3, 5; cytarabine 200 mg/m2 IV push bd days 1-8; thioguanine 100 mg/m2 bd oral days 1-10) or S-DAT 3+8 (daunorubicin 50 mg/m2 daily by slow IV push on days 1, 3, 5; cytarabine 100 mg/m2 IV push bd days 1-8; thioguanine 100 mg/m2 bd oral days 1-10) was given with or without gemtuzumab ozogamicin in an amount of 3 mg/m2. Consolidation therapy consisted of MACE (MACE: Amsacarine 100 mg/m2 daily by one hour infusion (in 5% dextrose on days 1-5); cytarabine 200 mg/m2 by daily continuous IV infusion days 1-5, Etoposide 100 mg/m2 daily by one hour IV infusion days 1-5) chemotherapy with or without gemtuzumab ozogamicin in an amount of 3 mg/m2. Patients who received gemtuzumab ozogamicin in courses 1 and 2 had delayed hematological recovery and VOD, one of whom died. The 6 mg/m2 dose of gemtuzumab ozogamicin was also associated with increased liver toxicity. It was concluded that 3 mg/m2 gemtuzumab ozogamicin can be given with H-DAT 3+10 in course 1 and in course 3 with MACE, but that two courses of gemtuzumab ozogamicin in induction or an increase of the dose of gemtuzumab ozogamicin to 6 mg/m2 is associated with increased toxicity and not recommended. Burnett, A. K. and Kell, J., “The Feasibility of Combining Immunoconjugate and Chemotherapy in AML,” Hematology J. (June 2002) Vol. 3, supp. 1, p. 156.
In another preliminary study to assess safety and efficacy, gemtuzumab ozogamicin was given to de novo and relapsed/refractory AML patients >60 years old in a combination therapy with cytarabine. Six patients were treated with cytarabine by continuous infusion in an amount of 100 mg/m2/day on days 1 to 7 and gemtuzumab ozogamicin in an amount of 6 mg/m2 on days 1 and 15. While the combination was well tolerated, four patients died. To reduce the duration of myelosuppression following induction therapy, gemtuzumab ozogamicin was administered on days 1 and 8 in an amount of 6 mg/m2 on day 1 and 4 mg/m2 on day 8. Of seven patients who were treated, three achieved complete remission. Durrant, S., et al., Proc. Amer. Soc. Clin. Oncol. (2002) 21:271a.
To assess the safety and efficacy of gemtuzumab ozogamicin as part of combination therapy for AML, a phase I/II study was developed in the United States of America combining gemtuzumab ozogamicin with cytarabine and daunorubicin. The phase I portion of the study began in October 2000 and a preliminary report was published at the 43rd American Society of Hematology Annual Meeting electronically on Nov. 6, 2001 and in print on Nov. 7, 2001. DeAngelo, D., et al., “Preliminary Report of the Safety and Efficacy of Gemtuzumab Ozogamicin (Mylotarg®) Given in Combination with Cytarabine and Daunorubicin in Patients with Acute Myeloid Leukemia”, Blood (2001) 98:199(b). That report described the treatment of three patients, one with de novo AML and two with relapsed/refractory AML, with cytarabine in an amount of 100 mg/m2/day by continuous infusion on days 1 to 7, daunorubicin in an amount of 45 mg/m2 on days 1 to 3, and gemtuzumab ozogamicin in an amount of 6 mg/m2 on day 4 (dosage group 1). The combination was well tolerated, no dose-limiting toxicity (DLT) was observed, and two patients achieved a remission. Three patients with relapsed/refractory AML then were enrolled in the next dosage group in which the dose of gemtuzumab ozogamicin was escalated to 9 mg/m2 (dosage group 2), with the combination well tolerated, but all three patients were nonresponders. Six additional patients, three with de novo AML and three with relapsed/refractory AML, were enrolled at the dosage level of 9 mg/m2. Therapy was again well tolerated, and no DLT was observed. There were, however, 2 episodes of grade 3 non-drug-related elevations of ALT/AST and 2 episodes of grade 4 non-drug-related dyspnea. All 3 patients with de novo AML achieved remission and recovered both an ANC >1500/L and platelets >100,000/L on days 26, 28, and 36, respectively. Patients then were enrolled in the next dosage group in which the cytarabine dose was increased to 200 mg/m2/day (dosage group 3). Infusion of the combination therapy was well tolerated, but DLT was observed in four of six patients enrolled in this group with one patient with refractory AML developing hepatic VOD soon after completing induction therapy and dying on day 28. Another patient with de novo AML died of cardiac arrest on day 24 and also had reversible grade 3 elevation of ALT. In light of the foregoing results, it was concluded that six additional patients would be enrolled in dosage group 1 to expand the safety data, and if the combination of cytarabine 100 mg/m2/day, daunorubicin 45 mg/m2, and gemtuzumab ozogamicin 6 mg/m2 would be found to be well tolerated in this expanded group, then the phase II portion of the study would begin and approximately 45 patients with de novo AML would be enrolled. DeAngelo, D., et al., supra. The efficacy of the combination of cytarabine 100 mg/m2/day, daunorubicin 45 mg/m2, and gemtuzumab ozogamicin 6 mg/m2 could not be determined based on the limited number of patients enrolled in the phase I portion of the study or the efficacy of this combination compared to the efficacy of standard chemotherapy for AML.
Myelodysplastic syndrome (MDS) is a group of syndromes (preleukemia, refractory anemias, Ph-negative chronic myelocytic leukemia, chronic myelomonocytic leukemia, agnogenic myeloid metaplasia) commonly seen in patients >50 years old. Its incidence is unknown, but it is increasing, probably in part due to the increasing proportion of elderly in the population and an increase in treatment-associated leukemias. Exposure to benzene and radiation may be related to its development. In the preleukemic phase of some of the secondary leukemias (e.g., after drug or toxic exposure), altered and defective cellular production may be seen with diagnostic features of myelodysplasia. The Merck Manual, Sec. 11, Ch. 138 (17th ed. 1999).
MDS is characterized by clonal proliferation of hematopoietic cells, including erythroid, myeloid, and megakaryocytic forms. The bone marrow is normal or hypercellular, and ineffective hematopoiesis causes variable cytopenias, the most frequent being anemia. The disordered cell production is also associated with morphologic cellular abnormalities in marrow and blood. Extramedullary hematopoiesis may occur, leading to hepatomegaly and splenomegaly. Myelofibrosis is occasionally present at diagnosis or may develop during the course of MDS. The MDS clone is unstable and tends to progress to AML. The prognosis of a patient with MDS is highly dependent on FAB classification and on any associated disease. Patients with refractory anemia or refractory anemia with sideroblasts are less likely to progress to the more aggressive forms and may die of unrelated causes. The Merck Manual, Sec. 11, Ch. 138 (17th ed. 1999).
There is no established treatment for MDS. Therapy is supportive with RBC transfusions, platelet transfusions for bleeding, and antibiotic therapy for infection. In some patients, cytokine therapy (erythropoietin to support red blood center needs, granulocyte colony-stimulating factor to manage severe symptomatic granulocytopenia, and, when available, thrombopoietin for severe thrombocytopenia) can serve as important hematopoietic support. Allogeneic bone marrow transplantation is not recommended for patients >50 years old. Colony-stimulating factors (e.g., granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor) increase neutrophil counts, and erythropoietin increases RBC production in 20 to 25% of cases, but survival advantage has not been shown. Response of MDS to AML chemotherapy is similar to that of AML, after age and karyotype are considered. The Merck Manual, Sec. 11, Ch. 138 (17th ed. 1999).
Thus, there is a need for an improved treatment for patients with acute leukemia or myelodysplastic syndrome which will produce a higher rate of complete remission, thereby increasing the survival prospects of such patients. It has been surprisingly been found that a combination therapy employing an anti-CD33 cytotoxic conjugate in combination with an anthracycline and a pyrimidine or purine nucleoside analog, in particular, gemtuzumab ozogamicin, daunorubicin, and cytarabine, respectively, a significant improvement in efficacy compared to the combination therapy of daunorubicin and cytarabine or to gemtuzumab ozogamicin alone.